| In response to many intracellular acute infections activated naive CD8+ T cells or Cytotoxic T-Lymphocytes (CTLs) undergo a transition into effector CTLs, gaining cytotoxic and chemotactic functions that allow them to effectively control an infection. During this period the effector population is not uniform. In particular, with regard to memory potential intrinsic differences result in some cells with higher potential to become memory CTLs. These differences reflect a cell fate decision that results in the majority of effector CTLs becoming terminally differentiated. The transcription factor T-BET was previously shown to drive terminal differentiation of CTLs in a gradient manner, with high amounts promoting terminal differentiation. However, the mechanisms by which high T-BET levels drive differentiation are not well understood. Expression profiling of WT and T-BET deficient CTLs revealed that terminally differentiated CTLs express high levels of the transcription factor, ZEB2 in a T-BET dependent manner. This thesis work aimed to determine what role, if any, ZEB2 has in effector CTL differentiation and whether T-BET requires ZEB2 to promote the terminal differentiation of effector CTLs.;We found that ZEB2 cooperates with T-BET, predominantly acting in terminally differentiated CTLs, by promoting a transcriptional program that drives differentiation, while suppressing pro-memory genes. Ectopic expression of high T-BET levels, in the absence of ZEB2, was insufficient to drive normal CTL differentiation, suggesting that these transcriptional regulators cooperate at some loci to regulate the transcriptional programming underlying terminal differentiation in CTLs. We also identified the transcription factor ZEB1 as a potential antagonistic partner to ZEB2, promoting memory precursor fates. Furthermore, we identify the microRNA 200 (miR-200) family as a regulator of CTL differentiation, in part mediated by its reciprocal regulation of ZEB2. Ectopic expression of members of the miR-200 family reduced Zeb2 expression, and largely resembled ZEB2 deficiency.;Together these data suggest that ZEB2 plays an important role in programming terminal differentiation and restricting memory precursor cell fates. |
